Prostaglandins play a major role in the inflammation process and the inhibition of prostaglandin production, especially production of PGG.sub.2, PGH.sub.2 and PGE.sub.2, has been a common target of antiinflammatory drug discovery. However, common non-steroidal antiinflammatory drugs (NSAIDs) that are active in reducing the prostaglandin-induced pain and swelling associated with the inflammation process are also active in affecting other prostaglandin-regulated processes not associated with the inflammation process. Thus, use of high doses of most common NSAIDs can produce severe side effects, including life threatening ulcers, that limit their therapeutic potential. An alternative to NSAIDs is the use of corticosteroids, which have even more drastic side effects, especially when long term therapy is involved.
Previous NSAIDs have been found to prevent the production of prostaglandins by inhibiting enzymes in the human arachidonic acid/prostaglandin pathway, including the enzyme cyclooxygenase (COX). The recent discovery of an inducible enzyme associated with inflammation (named "cyclooxygenase-2 (COX-2)" or "prostaglandin G/H synthase II") provides a viable target of inhibition which more effectively reduces inflammation and produces fewer and less drastic side effects.
The references below that disclose antiinflammatory activity, show continuing efforts to find a safe and effective antiinflammatory agent. The novel pyrroles disclosed herein are such safe and also effective antiinflammatory agents furthering such efforts. The substituted pyrrolyl compounds disclosed herein preferably selectively inhibit cyclooxygenase-2 over cyclooxygenase-1.
Pyrroles have been described for various uses, including the treatment of inflammation.
U.S. Pat. No. 5,219,856, to R. Olson, generically describes pyrrole-containing angiotensin-II inhibitors. U.S. Pat. No. 5,236,943, to Heitsch et al., generically describes pyrrole containing angiotensin-II inhibitors.
U.S. Pat. No. 5,128,485, to V. Kameswaran, describes a process for preparing 2-phenyl-5-trifluoromethylpyrroles. EP 492093, published Jul. 1, 1992, describes a similar process.
U.S. Pat. No. 5,032,590, to Hubsch et al., describes 1,2-diphenyl-3-(4-fluorophenyl)-5-isopropylpyrrole as an intermediate in the preparation of a hydroxylamine substituted pyrrole.
H. Stetter and M. Schreckenberg (Chem. Ber., 107, 2453 (1974)! describe the synthetic preparation of 1,2-diaryl pyrroles, and specifically, 2-(4-chlorophenyl)-5-methyl-1-phenylpyrrole. F. Cerreto, et al. Eur. J. Med. Chem, 27, 701 (1992)! describe the 1,5-diaryl-2-methylpyrroles as having anti-Candida activity. M. Scalzo et al. Il Farmaco Ed. Sc., 43, 665 (1988)! describe 1,5-substituted pyrroles as having antibacterial activity. M. Scalzo et al. Il Farrmaco Ed. Sc., 43, 677 (1988)! describe other 1,5-substituted pyrroles as having antibacterial activity. M. Scalzo et al. Eur. J. Med. Chem, 23, 587 (1988)! describe 2-methyl-5-(4-nitrophenyl)-1-phenylpyrroles as having antibacterial activity.
C. Gillet, et al Eur. J. Med. Chem, 11, 173 (1976)! describe the 1,5-diaryl-3-pyrrole acetic acids as having antiinflammatory activity. German Patent DE 2,261,965 describes 2-methyl-1-phenylpyrroles as having antiinflammatory activity. Belgian Patent 633,582 describes 1-aryl-5-(4-alkoxyphenyl)-2-pyrrole propanoic acids as anticholesterolaemic agents. G. Thiault et al. Il Farmaco Ed. Sc., 39, 524 (1984)! describe 1,5-substituted pyrroles as having analgesic and antiinflammatory activity. G. Thiault et al. Il Farmaco Ed. Sc., 39, 765 (1984)! describe other 1,5-substituted pyrroles as having analgesic and antiinflammatory activity. U.S. Pat. No. 4,694,018, issued to L. Chin, describes 1-(halophenyl)-5-phenyl-2-pyrrole propanoic acid derivatives as 5-lipoxygenase inhibitors. U.S. Pat. No. 5,096,919, issued to Wasley et al., describes 1-pyrrole phenyl hydroxamic acid derivatives as 5-lipoxygenase inhibitors.
U.S. Pat. No. 4,267,184, issued to S. Cherkofsky, describes 4,5-aryl-2-thiopyrroles as antiinflammatory agents. U.S. Pat. No. 4,267,190, issued to S. Cherkofsky, describes 4,5-aryl-2-methanethiolpyrroles as antiinflammatory agents. U.S. Pat. No. 4,335,136, issued to S. Cherkofsky, describes 4,5-aryl-2-methanaminepyrroles as antiinflammatory agents. U.S. Pat. No. 4,267,184, issued to S. Cherkofsky, describes 4,5-aryl-2-halopyrroles as antiinflammatory agents. U.S. Pat. No. 3,531,497, issued to G. Youngdale, describes 2,4,5-triphenylpyrroles as antiinflammatory agents. U.S. Pat. No. 4,267,184, issued to S. Cherkofsky, describes 4,5-phenylpyrroles as antiinflammatory agents. U.S. Pat. No. 5,474,995, issued to Ducharme et al., describes 4,5-phenylpyrroles as cyclooxygenase-2 inhibitors. W. Wilkerson et al. Med. Chem. Res,. 5, 399 (1995)! describe 4,5-diarylpyrroles as COX-2 inhibitors. W. Wilkerson et al. J. Med. Chem., 38, 3895 (1995)! describe 4,5-diarylpyrroles as COX-2 inhibitors. PCT patent document W094/15932, published Jul. 21, 1994, describes 3,4-diphenylpyrroles as inhibiting cyclooxygenase-2.
U.S. Pat. No. 5,187,185, to outcalt, et al., describes substituted 1-arylpyrroles as pesticides. European patent document EP 372,982, published Jun. 13, 1990, describes similar compounds.
U.S. Pat. No. 3,427,305, to L. Chinn, describes 1-4-(aminosulfonyl)phenyl!pyrrole propanoic acids as being antiinflammatory. Specifically, 1-(4-(aminosulfonyl)phenyl!-5-(4-fluorophenyl)-2-pyrrole propanoic acid is described.
British patent GB 1,263,940 describes 1-phenylpyrroles as having antiinflammatory activity. Specifically, 4-2-methyl-5-phenylpyrrol-1-yl!benzenesulfonamide is described.
The invention's pyrrolyl compounds are found to show usefulness as antiinflammatory agents with minimal side effects.